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Driver mutations lung cancer

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https://www.readbyqxmd.com/read/28821559/synergy-of-wee1-and-mtor-inhibition-in-mutant-kras-driven-lung-cancers
#1
Josephine Hai, Shengwu Liu, Lauren Bufe, Khanh Do, Ting Chen, Xiaoen Wang, Christine Ng, Shuai Li, Ming-Sound Tsao, Geoffrey I Shapiro, Kwok-Kin Wong
Purpose:KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. <p>Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28814544/direct-detection-of-early-stage-cancers-using-circulating-tumor-dna
#2
Jillian Phallen, Mark Sausen, Vilmos Adleff, Alessandro Leal, Carolyn Hruban, James White, Valsamo Anagnostou, Jacob Fiksel, Stephen Cristiano, Eniko Papp, Savannah Speir, Thomas Reinert, Mai-Britt Worm Orntoft, Brian D Woodward, Derek Murphy, Sonya Parpart-Li, David Riley, Monica Nesselbush, Naomi Sengamalay, Andrew Georgiadis, Qing Kay Li, Mogens Rørbæk Madsen, Frank Viborg Mortensen, Joost Huiskens, Cornelis Punt, Nicole van Grieken, Remond Fijneman, Gerrit Meijer, Hatim Husain, Robert B Scharpf, Luis A Diaz, Siân Jones, Sam Angiuoli, Torben Ørntoft, Hans Jørgen Nielsen, Claus Lindbjerg Andersen, Victor E Velculescu
Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb...
August 16, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28806950/precision-medicine-approaches-to-lung-adenocarcinoma-with-concomitant-met-and-her2-amplification
#3
Doo-Yi Oh, Kyungsoo Jung, Ji-Young Song, Seokhwi Kim, Sang Shin, Yong-Jun Kwon, Ensel Oh, Woong-Yang Park, Sang Yong Song, Yoon-La Choi
BACKGROUND: Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS: We performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations...
August 10, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28797845/the-hsp90-inhibitor-nvp-auy922-attenuates-intrinsic-pi3k-inhibitor-resistance-in-kras-mutant-non-small-cell-lung-cancer
#4
Kang-Seo Park, Hannah Yang, Junyoung Choi, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Hanwool Jeon, Sang-We Kim, Dae Ho Lee
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway...
August 7, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28794371/successful-treatment-with-alectinib-for-choroidal-metastasis-in-anaplastic-lymphoma-kinase-rearranged-non-small-cell-lung-cancer
#5
Tomoko Funazo, Kyohei Morita, Naoya Ikegami, Chisato Konishi, Satoshi Nakao, Ryo Ariyasu, Masato Taki, Kazuhiko Nakagawa, Moon Hee Hwang, Chie Yoshimura, Toshiaki Wakayama, Yasuo Nishizaka
Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy...
August 10, 2017: Internal Medicine
https://www.readbyqxmd.com/read/28765324/glesatinib-exhibits-antitumor-activity-in-lung-cancer-models-and-patients-harboring-met-exon-14-mutations-and-overcomes-mutation-mediated-resistance-to-type-i-met-inhibitors-in-nonclinical-models
#6
Lars Engstrom, Ruth Aranda, Matthew Lee, Elizabeth A Tovar, Curt Essenburg, Zachary B Madaj, Harrah Chiang, David Briere, Jill Hallin, Pedro P Lopez-Casas, Natalia Banos, Camino Menéndez, Manuel Hidalgo, Vanessa Tassell, Richard Chao, Darya I Chudova, Richard B Lanman, Peter Olson, Lyudmila Bazhenova, Sandip P Patel, Carrie R Graveel, Mizuki Nishino, Geoffrey I Shapiro, Nir Peled, Mark M Awad, Pasi A Janne, James G Christensen
MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations.  We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28763691/treatment-of-elderly-patients-or-patients-who-are-performance-status-2-ps2-with-advanced-non-small-cell-lung-cancer-without-epidermal-growth-factor-receptor-egfr-mutations-and-anaplastic-lymphoma-kinase-alk-translocations-still-a-daily-challenge
#7
REVIEW
Chunxia Su, Fei Zhou, Jiqiao Shen, Jing Zhao, Mary O'Brien
Cytotoxic chemotherapy remains the core treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) with tumours that do not have actionable molecular alterations, such as epidermal growth factor receptor (EGFR)-sensitising mutations, anaplastic lymphoma kinase (ALK) translocations or ROS1 translocations. Age and performance status (PS) are two pivotal factors to guide treatment decisions regarding the use of chemotherapy in lung cancer patients. Lung cancer is predominantly a disease of the elderly, with more than two-thirds of patients aged ≥65 years, the current definition of 'elderly'...
July 29, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28757336/double-trouble-a-case-series-on-concomitant-genetic-aberrations-in-nsclc
#8
REVIEW
Nele Van Der Steen, Yves Mentens, Marc Ramael, Leticia G Leon, Paul Germonpré, Jose Ferri, David R Gandara, Elisa Giovannetti, Godefridus J Peters, Patrick Pauwels, Christian Rolfo
Several oncogenic drivers have been identified in non-small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene...
July 6, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28755461/variation-in-organ-specific-pik3ca-and-kras-mutant-levels-in-normal-human-tissues-correlates-with-mutation-prevalence-in-corresponding-carcinomas
#9
Barbara L Parsons, Karen L McKim, Meagan B Myers
Large-scale sequencing efforts have described the mutational complexity of individual cancers and identified mutations prevalent in different cancers. As a complementary approach, allele-specific competitive blocker PCR (ACB-PCR) is being used to quantify levels of hotspot cancer driver mutations (CDMs) with high sensitivity, to elucidate the tissue-specific properties of CDMs, their occurrence as tumor cell subpopulations, and their occurrence in normal tissues. Here we report measurements of PIK3CA H1047R mutant fraction (MF) in normal colonic mucosa, normal lung, colonic adenomas, colonic adenocarcinomas, and lung adenocarcinomas...
July 29, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28745554/anaplastic-lymphoma-kinase-rearrangements-in-non-small-cell-lung-cancer-novel-applications-in-diagnostics-and-treatment
#10
Rodney E Shackelford, Junaid M Ansari, Eric X Wei, Jonathan S Alexander, James Cotelingam
The ALK gene, first identified as an anaplastic large cell lymphoma driver mutation, is dysregulated in nearly 20 different human malignancies, including 3-7% of non-small-cell lung cancers (NSCLC). In NSCLC, ALK commonly fuses with the EML4, forming a constitutively active tyrosine kinase that drives oncogenic progression. Recently, several ALK-inhibiting drugs have been developed that are more effective than standard chemotherapeutic regimens in treating advanced ALK-positive NSCLC. For this reason, molecular diagnostic testing for dysregulated ALK expression is a necessary part of identifying optimal NSCLC treatment options...
August 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28743157/her2-mutations-in-lung-adenocarcinomas-a-report-from-the-lung-cancer-mutation-consortium
#11
Rathi N Pillai, Madhusmita Behera, Lynne D Berry, Mike R Rossi, Mark G Kris, Bruce E Johnson, Paul A Bunn, Suresh S Ramalingam, Fadlo R Khuri
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) mutations have been reported in lung adenocarcinomas. Herein, the authors describe the prevalence, clinical features, and outcomes associated with HER2 mutations in 1007 patients in the Lung Cancer Mutation Consortium (LCMC). METHODS: Patients with advanced-stage lung adenocarcinomas were enrolled to the LCMC. Tumor specimens were assessed for diagnosis and adequacy; multiplexed genotyping was performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories to examine 10 oncogenic drivers...
July 25, 2017: Cancer
https://www.readbyqxmd.com/read/28740365/spotlight-on-ceritinib-in-the-treatment-of-alk-nsclc-design-development-and-place-in-therapy
#12
REVIEW
Mariacarmela Santarpia, Maria Grazia Daffinà, Alessandro D'Aveni, Grazia Marabello, Alessia Liguori, Elisa Giovannetti, Niki Karachaliou, Maria Gonzalez Cao, Rafael Rosell, Giuseppe Altavilla
The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib's efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28698358/integrative-cage-and-dna-methylation-profiling-identify-epigenetically-regulated-genes-in-nsclc
#13
Masafumi Horie, Bogumil Kaczkowski, Mitsuhiro Ohshima, Hirotaka Matsuzaki, Satoshi Noguchi, Yu Mikami, Marina Lizio, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R R Forrest, Daiya Takai, Yoko Yamaguchi, Patrick Micke, Akira Saito, Takahide Nagase
Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 non-small cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells...
July 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28693444/the-value-of-ultrasound-guided-biopsy-of-fluorodeoxy-glucose-positron-emission-tomography-fdg-pet-positive-supraclavicular-lymph-nodes-in-patients-with-suspected-lung-cancer
#14
Lennart Werner, Franziska Aebersold Keller, Ujwal Bhure, Justus Egidius Roos, Katharina Tornquist, Maria Del Sol Pèrez-Lago, Oliver Gautschi, Klaus Strobel
BACKGROUND: Accurate lymph node staging is essential for adequate prognostication and therapy planning in patients with non-small cell lung cancer (NSCLC). FDG-PET/CT is a sensitive tool for the detection of metastases, including non-palpable supraclavicular lymph node (SCLN) metastases. Histological proof of metastatic spread and mutation analysis is crucial for optimal staging and therapy. The aim of this study was to investigate the value of ultrasound-guided fine needle aspiration cytology (FNAC) and core biopsy (CB) of FDG active, non-palpable SCLN's in patients with suspicion for lung cancer...
July 11, 2017: BMC Medical Imaging
https://www.readbyqxmd.com/read/28685087/heterogeneity-in-the-colorectal-primary-tumor-and-the-synchronous-resected-liver-metastases-prior-to-and-after-treatment-with-an-anti-egfr-monoclonal-antibody
#15
Daniela Adua, Francesca Di Fabio, Giorgio Ercolani, Michelangelo Fiorentino, Elisa Gruppioni, Annalisa Altimari, Fabiola Lorena Rojas Limpe, Nicola Normanno, Antonio Daniele Pinna, Carmine Pinto
Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody...
July 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28677170/inactivating-mutations-and-hypermethylation-of-the-nkx2-1-ttf-1-gene-in-non-tru-type-lung-adenocarcinomas
#16
Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Yuji Sakuma, Azusa Yamato, Toshihide Ueno, Shinya Kojima, Tomoki Shibano, Yasuyuki Hosono, Masahito Kawazu, Yoshihiro Yamashita, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Takashi Takahashi, Hiroyuki Mano, Toshiro Niki
The major driver mutations of lung cancer, the EGFR mutations and EML4-ALK fusion, are mainly detected in terminal respiratory unit (TRU)-type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non-TRU-type lung cancer, we conducted whole-exome sequencing on 43 non-TRU-type lung adenocarcinomas based on morphology (17 acinar, 9 solid, 2 enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology)...
July 5, 2017: Cancer Science
https://www.readbyqxmd.com/read/28676214/dna-mismatch-repair-deficiency-in-surgically-resected-lung-adenocarcinoma-microsatellite-instability-analysis-using-the-promega-panel
#17
Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Eiichi Sato, Shinji Kohsaka, Takuo Hayashi, Shigehisa Kitano, Toshihide Uneno, Shinya Kojima, Kengo Takeuchi, Hiroyuki Mano, Kenji Suzuki
OBJECTIVES: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas. MATERIALS AND METHODS: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28669334/therapeutic-approaches-for-the-treatment-of-epidermal-growth-factor-receptor-mutated-lung-cancer
#18
Dhaval Sanchala, Lokesh K Bhatt, Kedar S Prabhavalkar
Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal growth factor receptor (EGFR) is the most regular driver mutation encountered in non-small cell lung cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma...
June 23, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28668874/immunological-status-may-predict-response-to-nivolumab-in-non-small-cell-lung-cancer-without-driver-mutations
#19
Makoto Nakao, Hideki Muramatsu, Yusuke Kagawa, Yuto Suzuki, Yusuke Sakai, Ryota Kurokawa, Kohei Fujita, Hidefumi Sato
BACKGROUND/AIM: It remains challenging to select patients with non-small cell carcinoma (NSCLC) for nivolumab monotherapy. We evaluated whether early termination of nivolumab monotherapy correlated with pretreatment neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI). PATIENTS AND METHODS: Twenty patients received nivolumab monotherapy for NSCLC with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) during 2016...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28668385/driving-to-cancer-on-a-four-lane-expressway
#20
Lorenzo Galluzzi, Ilio Vitale
Recent findings from a prospective clinical study involving multiregion whole-exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome.
June 28, 2017: Trends in Genetics: TIG
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